The hedgehog gene family encodes secreted proteins important in many developmental patterning events in both vertebrates and invertebrates. Members of the Hedgehog family of signaling molecules mediate many important short and long range patterning processes during invertebrate and vertebrate development. To date, the combined screening of mouse genomic and cDNA libraries has identified 3 mammalian hh counterparts referred to as Desert hedgehog (Dhh), Sonic hedgehog (Shh) and Indian hedgehog (Ihh), which also exists in other mammals.
The Hh pathway generally includes an Hh ligand (e.g., DHH, IHH and/or SHH) which binds an Hh ligand receptor (e.g., PTCH/ptc), resulting in activation of SMO (a G protein coupled receptor-like polypeptide), which transduces the Hh signal downstream, resulting in activation of additional members of the Hh pathway (e.g., Fused), including Hh pathway stimulated transcription factors (e.g., members of the GLI family of transcription factors). Also associated with the Hh pathway activity are transcriptional targets, inclduing, for example, nestin and BMI-1, which can be induced by activated GLI transcription factor.
Ligands:
The vertebrate family of hedgehog genes includes at least four members, three of which, Desert hedgehog (Dhh), Sonic hedgehog (Shh) and Indian hedgehog (Ihh) apparently exist in all vertebrates and a fourth member, tiggie-winkle hedgehog (Thh) which appears specific to fish.
Desert hedgehog (Dhh): is expressed principally in the testes, both in mouse embryonic development and in the adult rodent and human.
Indian hedgehog (Ihh): is involved in bone development during embryogenesis and in bone formation in the adult.
Sonice hedgehog (Shh): is primarily involved in morphogenic and neuroinductive activities.
Receptors:
The interaction of a hedgehog protein with one of its cognate receptors, patched (ptc) sets in motion a cascade involving the activaiton and inhibition of downstream effectors, the tulimate consequence of which is, in some instances, a detectable change in the transcription or translation of a gene. Hedgehog and its cognate receptor pathed (ptc) are expressed in the epithelial and/or mesenchymal cell components of the skin (i.e., the hair follicle).
Patched 1 (PTCH1): is a 12-transmembranece domain (12-TM) protein located at least in part on the plasma membrane. In its unliganded state, PTCH1 can suppress the activity of Smoothened (SMOH), a 7-TM protein predominentaly located in the membrane of entracellular endosomes. However, upon binding of HH, PTCH1 can no longer supress SMOH, ultimately leading to activation of the transcription factors GLI1, GLI2, and GLI3, which in turn upregulate expression of certain genes, thereby stimulating the cell to (e.g., proliferate).
Patched 2 (PTCH2): may act similarly to PTCH1 in certain circumstances.
Targets:
Bone morphogenic proteins (BMPs): are multifunctional cytokines, which are members of the transforming growth factor-beta superfamily. They regualte cellular proliferation, differentation, apoptosis of various cell types. Activities of BMPs are extracellularly regulated by BMP-binding proteins such as Noggin, Chordin, Gremlin Cerberus and Xnr-3. BMPs bind to two different types of serine-threonine kinase receptors, type I and type II.
Wingless (Wnt): The Wnt genes are targets of the HH pathway. Wnt proteins are secreted growth factors which are involved in the regulation of epithelial cell proliferation and differentiation in the lung during embryonic development. Dischevelled-1 (Dvl-1) is the murine homolog of the fly Dsh gene and functions to transmit signals form the Wnt receptor, Frizzled, to the cytoplasm, where it regulates the kinase activity of a well known serine/threonine kinase GSK-3b.
–WNT-beta-catenin signalling: is an evolutionarilly conserved signalling pathway involved in b a broad range of cell processes including oncogenesis and embryogenesis. Canonical WNT-beta-caterenin signaling is initated by binding of a WNT family protein to cell surface receptors that activate signal transduction, resulting in nuclear translocation of Bteta carenin and transcriptional activation. It has recently emerged as an oncogenic signaling pathway that impedes the initiation of de novo antitumour immune respoens.
Involvement in Disease:
The Hedgehog (Hh) pathway activity has been reported to be involved in a variety of cancers (WO 2009/126840). For example, it is reportely elevated in prostate tumor cells as compared to corresponding normal cells of the organ with the tumor and agents that decrease the Hh pathway activity inhibit proliferation of prostate tumor cells (WO 2005/032343).